The regulation of blood pressure in mammals, especially humans, is an important medical problem. Hypertension, which is an abnormally high level of blood pressure, is a disease of particular concern, along with hypotension, which is low blood pressure. Therefore, the discovery of substances that can aid in the detection and treatment of blood pressure abnormalities is an important one. The present invention encompasses a class of peptides and their antibodies which affect the regulation of blood pressure.
A physiological pathway believed to affect blood pressure is as follows. Angiotensinogen also known as renin substrate, is acted upon by an enzyme, called renin, to produce angiotensin I. Angiotensin I is a relatively inactive decapeptide; in other words, angiotensin I does not have a major hormonal effect on blood pressure. However, angiotensin I is converted to angiotensin II by an enzyme called angiotensin converting enzyme. Angiotensin II, an octapeptide, is often at elevated levels in those individuals with hypertension and its action at these elevated levels causes blood vessel constriction and water retention, both of which are associated with hypertension. By modification or blockage of the peptides or enzymes in this pathway, the level of blood pressure can be controlled.
The pathway is also shown in the following diagram: ##STR4##
Various peptides or angiotensin analogs have been prepared and disclosed. An extensive review of known analogs is found in Khosla, et al., "Structure-Activity Relationship in Angiotensin II Analogs", Angiotensin (Page and Bumpus eds), Handbook of Experimental Pharmacology, Vol. 34, 126-161 (1974). Other analogs are described in U.S. Pat. No. 4,179,433 and 4,209,442, which analogs have the following amino acid sequence: EQU W-ARG-VAL-TYR-ILE-HIS-PRO-Z
wherein:
W is a radical derived from an aliphatic .alpha.-aminooxycarboxylic acid, hydroxyacetyl, or a-hydroxypropyl; and PA1 Z is a radical derived from an aliphatic .alpha.-amino-carboxylic acid, leucyl, isoleucyl, alanyl, or threonyl. PA1 Y is --OH, --NH.sub.2, or --PRO; PA1 AA.sup.1 is LYS, GLU, GLN, pGLU, .beta.ALA, PRO, PRO--OH, PIC, or AIB; PA1 AA.sup.2 is VAL, LEU, ILE, MET, or AIB; PA1 AA.sup.3 is ASP, TYR, GLU, HIS, or PHE; PA1 AA.sup.4 is VAL, MET, ILE, LEU, or AIB; PA1 AA.sup.5 is TYR, HIS, or GLU; PA1 AA.sup.6 is ALA, PRO, SER, .beta.ALA, PRO--OH, or AIB; and PA1 AA.sup.7 is VAL, LEU, ILE, or AIB; PA1 AA.sup.1 is LYS, GLU, or GLN; PA1 AA.sup.2 is VA or LEU; PA1 AA.sup.3 is ASP, TYR, or GLU; PA1 AA.sup.4 is VAL, LET, ILE, or LEU; PA1 AA.sup.5 is TYR, HIS, or GLU; PA1 AA.sup.6 is ALA, PRO, or SER; and PA1 AA.sup.7 is VAL or LEU.
U.S. Pat. No. 4,302,386 describes the production of antibodies raised against hormones.